Review Articles

Cyclin-dependent kinase (CDK) 4/6 inhibitors in combination with endocrine therapy have become the standard-of-care therapy for patients with advanced-stage hormone receptor-positive breast cancer. However, this success has created several challenges, such as the need to better understand resistance to these agents and develop novel therapies accordingly. Here, the authors provide an update on the clinical activity of the established CDK4/6 inhibitors along with a summary of ongoing research efforts attempting to address the new challenges created by the success of these agents.

Patients with advanced-stage urothelial cancer (aUC) continue to have poor long-term survival outcomes. However, developments in the past 5 years, most notably the availability of maintenance therapy with the anti-PD-1 antibody avelumab, are beginning to change this issue. In this Review, the authors provide an overview of the treatment of patients with aUC, including considerations of the various promising new therapeutic modalities and how they might improve clinical outcomes.

Identifying patients who are likely to benefit from immune-checkpoint inhibitors remains one of the major challenges in immunotherapy. Cancer immunogenomics is an emerging field that bridges genomics and immunology. The authors of this Review provide an overview of the computational approaches currently available to analyse bulk tissue and single-cell sequencing data from cancer, stromal and immune cells.

Hepatocellular carcinoma (HCC) is among the most common causes of cancer-related death globally, and despite improvements in prevention and treatment strategies, continued increases in HCC incidence and mortality are predicted. Cirrhosis remains the major risk factor for HCC, although the underlying aetiology is shifting from virus-related to non-viral liver diseases. In this Review, the authors discuss the changing trends in HCC epidemiology and their implications for screening, prevention and therapy, including opportunities to further improve the management of patients with, or at high risk of, HCC.

According to the precision oncology paradigm, cancer therapies are increasingly being matched to specific sensitizing alterations using a biomarker-directed approach. However, the criteria for determining the actionability of molecular alterations and selecting matched treatments evolve over time. Molecular tumour boards (MTBs) have emerged as means to capitalize on the collective knowledge of various experts to interpret molecular-profiling data and to eliminate subjectivity in treatment selection. This Review describes the components, processes and increasingly important role of MTBs in optimizing the implementation of precision oncology in both clinical trials and clinical practice, as well as current and future considerations for ensuring the sustainability of MTBs and expanding their outreach to underserved populations.

Ovarian carcinoma is a highly heterogeneous tumour type, both spatially and temporally. As a consequence, these carcinomas are often associated with poor outcomes. Ovarian carcinoma comprises various subtypes with distinct complex molecular features. The authors of this Review discuss the molecular, cellular and anatomical heterogeneity of ovarian carcinoma, and outline the current and future treatment strategies for this malignancy.

The availability of regimens containing one or more immune-checkpoint inhibitors (ICIs) has improved the outcomes in patients with advanced-stage hepatocellular carcinoma. However, clinical benefit from these regimens is difficult to predict, indicating the need for novel biomarkers. In this Review, the authors describe the available evidence on biomarkers to guide the use of ICIs in these patients and discuss promising future research directions.

The TAM (TYRO3, AXL and MERTK) family receptor tyrosine kinases (RTKs) have diverse cancer-promoting functions in malignant cells as well as immune cells and other cell types in the tumour microenvironment, presenting an attractive opportunity for both direct and immune-mediated therapeutic activity manifest through inhibition of a single target. Accordingly, a variety of agents designed to selectively target TAM RTKs are entering clinical testing. This Review provides an essential guide to the TAM RTKs for clinicians. The authors comprehensively review the various roles of TAM RTKs in cancer, the evidence supporting their potential as therapeutic targets, and the translational development of TAM-targeted agents as cancer treatments.

Despite improved outcomes owing to advances in systemic targeted therapies, patients with brain metastases from oncogene-driven non-small-cell lung cancer continue to have a poor prognosis. This situation largely reflects the limited central nervous system (CNS) penetrance of most targeted therapies, a limitation that is beginning to be addressed with the development of later-generation agents. In this Review, the authors describe the CNS activity of targeted therapies for patients with oncogene-driven non-small-cell lung cancers, including discussions of novel agents with improved CNS penetrance and the potential of intrathecal administration for patients with leptomeningeal disease.

In oncology, mRNA–lipid nanoparticles (LNPs) have been used either to achieve intratumoural expression of immune-stimulating cytokine combinations or as cancer vaccines, and new strategies are in development to enable the selective delivery of payloads into cancer cells previously considered unreachable. The authors of this Review present various approaches for delivering mRNA–LNPs to tumours and discuss improvements that will improve the selective targeting of cancer cells with mRNA–LNPs.

Advances over the past decade have established a prominent role of the gut microbiota in the modulation of immune homeostasis and function, including in patients with cancer receiving immune-checkpoint inhibitors. In this Review, the authors summarize current knowledge of the role of the microbiota in this context, describe several methods of modulating the microbiota clinically to improve patient outcomes, and highlight important future directions in this expanding area of research.

Several trials are testing immune-checkpoint inhibitors (ICIs), alone or in combination with chemotherapy, in patients with resectable non-small-cell lung cancer as an adjuvant, neoadjuvant or perioperative approach. However, the optimal use of ICIs with curative intent in patients with early stage non-small-cell lung cancer remains unclear. The authors of this Review discuss the current trial landscape and discuss challenges and opportunities.

Advances in the treatment of childhood cancers have substantially improved cure rates, although the gains in survival are offset by an elevated burden of morbidities and an excess risk of early death owing predominantly to the adverse effects of therapy. In this Review, the authors summarize the evolution of paediatric cancer therapies over the past five decades as well as the associated landscape of treatment-related late and/or long-term health conditions experienced by childhood cancer survivors. In addition, they discuss strategies that are being explored to reduce the overall burden and consequences of these morbidities with the ultimate aim of improving not only the quantity but also the quality of life-years gained for this large, medically vulnerable population.

Lung cancer is the commonest cancer globally. Reflecting patterns of smoking and other risk factor exposures, both the incidence of and mortality from lung cancer are highest in economically developed countries. Nonetheless, developing and less economically developed countries are likely to have the biggest increases in lung cancer in the coming years. In this Review, the authors describe the global epidemiology of lung cancer, and how changes in exposures, socioeconomic status, public health interventions and better treatment strategies are influencing both the incidence of and mortality from lung cancer.

Despite advances in drug development for patients with lymphoma over the past decades, the identification of biomarkers for treatment selection remains an unmet need. The authors of this Review provide an overview of quantitative PET-based biomarkers in this patient population and discuss the challenges and opportunities in the integration of these biomarkers in clinical trials and the routine management of patients with lymphoma.

Many studies attempting to identify biomarkers for predicting of immune-checkpoint inhibitor (ICI) efficacy have led to the description of Gut OncoMicrobiome Signatures (GOMS). Several GOMS support an association between oncogenesis and intestinal dysbiosis, and other GOMS are shared between patients with several cancer subtypes and individuals with seemingly unrelated chronic inflammatory disorders. The authors of this Review discuss these patterns as well as the findings from a meta-analysis of GOMS associated with clinical benefit from ICIs, and propose practical guidelines to incorporate GOMS in decision-making in immuno-oncology.

Immune-checkpoint inhibitors (ICIs) and other immunotherapies have revolutionized the treatment of patients with cancer. Nonetheless, most patients do not derive durable benefit, indicating a need for biomarkers to guide treatment selection. In this Review, the authors describe the role of antigen presentation in response to ICIs and other immunotherapies, with a focus on the role of molecular and/or genomic alterations affecting antigen presentation.

Advances in technology have enabled the development of several novel antibody–drug conjugates (ADCs) with encouraging clinical activity in patients with advanced-stage solid tumours. Indications for these therapies are expanding rapidly to earlier lines of therapy. Nonetheless, the toxicities of these various agents are not trivial and can be fatal, even in patients with early stage disease. In this Review, the authors summarize the toxicities of ADCs in patients with solid tumours both as monotherapies and in combination with other agents and discuss various ongoing research efforts attempting to optimize the therapeutic index of these agents.

Radiotherapy has several key attributes that make it an attractive combination partner for immunotherapy; however, numerous clinical trials investigating the combination of these two treatment modalities have failed to demonstrate clear improvements in patient outcomes. In this Review, Galluzzi and colleagues discuss the evidence indicating that radiotherapy administered according to standard schedules and target volumes might impair immune fitness and, therefore, propose that adaptation of the radiotherapy regimens to immunotherapy (and not vice versa) might synergistically enhance the antitumour immune response to achieve meaningful clinical benefits.

Long-term survival rates of patients with gastric cancer remain low, particularly in Western countries. This lack of progress, among other aspects, is likely to reflect a focus on empirical approaches that fail to account for the heterogeneity of gastric cancers. In this Review, the authors summarize the available evidence on the management of patients with early stage gastric cancers, with an emphasis on understanding the underlying biology in order to improve the outcomes in patients with these historically difficult-to-treat tumours.